The long-term research objective of this KO1 application is to define the role of the iron exporter Ferroportin 1 (Fpn1) in mammalian iron homeostasis. Fpn1 functions as a transmembrane iron exporter, and is important for normal development in zebrafish, where it is needed for transfer of iron from the yolk sac to developing erythrocytes. In contrast, the role of Fpn1 in mammals has not been established. We have previously demonstrated that Fpn1 is expressed in tissues that are key players in mammalian iron absorption and storage, including placenta, intestine, liver and reticuloendothelial macrophages. In addition, we have identified a missense mutation in Fpn1 that is associated with the iron overload disorder autosomaldominant hemochromatosis. Based upon our studies of Fpn1 in humans and mice, and the requirement for Fpn1 in zebrafish, we hypothesize that Fpn1 is critically involved in the export of iron from mammalian cells functioning in iron transport and storage. We plan to test our hypothesis by using gene-targeting strategies. The specific aims of this proposal are: 1) to employ a Fpn1 knock-out mouse model to characterize the requirement for Fpn1 in mice and the interaction of Fpn1 with other iron metabolism genes, 2) to define the role of Fpn1 in individual tissues using a conditional knockout strategy, and 3) to create and characterize a mouse model of the human iron overload disorder autosomal dominant hemochromatosis. In the long term, knowledge generated from the study of these mouse models could help us to better understand and treat diseases of iron homeostasis such as hemochromatosis, iron deficiency anemia and the anemia of chronic disease. The candidate's overall career goal is to study mammalian iron homeostasis as an independent academic scientist. This award will provide the candidate with a period of mentored research experience during which she will develop an independent research program. Dr. Nancy Andrews will mentor the candidate during the period of the award. As an expert in the field of iron metabolism, Dr. Andrews is well equipped to assist the candidate with the development of both the knowledge base and the resources required for her transition to full independence. During the period of the award the candidate will also expand her technical skills in the areas of mouse genetics, iron metabolism and developmental biology.